EGFR-Targeted Micelles-in-Lipopolymersome Nanocarriers for Overcoming Drug Resistance in Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) remains a therapeutic challenge due to its aggressive nature, limited treatment options, and propensity for developing multidrug resistance (MDR). To overcome these limitations, a novel micelles‑in‑lipopolymersome nanocarrier system is developed herein for targeted drug delivery. Specifically, an epidermal growth factor receptor (EGFR)‑targeted EGF peptide is conjugated to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE‑PEG‑NH₂) and subsequently incorporated into micelles, which significantly reduces the critical micelle concentration (CMC) and enhances the structural stability. The paclitaxel (PTX)‑loaded micelles (designated Micelle@PTX) exhibit pronounced pH-sensitive behavior, being less stable under acidic conditions, thereby facilitating rapid drug release in a tumor-like microenvironment. To further improve its stability and control the drug release, the Micelle@PTX is encapsulated within lipopolymersome to obtain Lipo‑Micelle@PTX particles with sizes ranging from 120 to 150 nm. Notably, the as-fabricated system effectively co‑delivers hydrophobic PTX and hydrophilic Irinotecan (CPT‑11), thereby illustrating its versatility for combination chemotherapy. In vitro release experiments demonstrate that both PTX and CPT‑11 are released more rapidly at pH 6.5 than at pH 7.4. Cellular uptake studies, supported by confocal microscopy and FACS analysis, reveal enhanced internalization of the EGFR‑targeted nanocarriers in drug‑resistant BT‑20 LUC/MDR cells, thus resulting in improved cytotoxicity compared to free PTX. Preliminary in vivo studies further demonstrate that Lipo‑Micelle@PTX significantly inhibits tumor growth compared to PTX alone, without inducing detectable systemic or organ toxicity. This study presents a promising platform for overcoming drug resistance in TNBC, with potential implications for targeted cancer therapy and improved clinical outcomes.